This section provides background information related to the present disclosure, which is not necessarily prior art - especially the selection, emphasis, and combination of and commentary on matters discussed. Separate and distinct topics addressed for background in this section include: 1) the traditional and current practice of pharmaceutical “compounding,” 2) benefits and challenges of combination drugs or “polypills,” whether manufactured or compounded, 3) “inkjet” based dispensing approaches for customizing drug oral dosage forms, and 4) current “micro-dosing” technologies for expediting manufacturability of pills for clinical trials.
Pharmaceutical “compounding” is when a pharmacist prepares medication uniquely for a particular patient, based on a physician's prescription. Before the prevalence of mass-produced drugs, this was a very common practice, but now it has largely been relegated to special cases where a mass-produced version of a drug is either unavailable or unsuitable for a patient. Provided that each compounded medication is uniquely prepared for an individual patient pursuant to a physician's order, compounding generally falls outside the jurisdiction of the FDA and instead within the regulation of the practice of Pharmacy under relevant state law. This line is not always clear, but there is strong general support for maintaining the flexibility needed to personalize medication at the pharmacy level and likewise not unduly bias physicians towards prescribing mass-produced products or dosage levels. But if the “compounding” is not for just one patient/customer but prepared in anticipation of multiple similar prescriptions, it may cross the line into “manufacturing” —and thus subject to such regulations.
Most compounding is either manual or partially-automated with the help of certain tools or equipment. So-called Automated Compounding Devices (ACDs), having full automation, exist at this time only for parenteral/intravenous (I.V.) medications, which are prepared as comparatively high-volume liquid solutions administered from bags (typically in a hospital). There is a noteworthy distinction between “reconstitution” which is performed according to a manufacturer's instruction versus “compounding” which is performed according to a doctor's prescription. Compounding of solid oral dosage forms is relatively rare today for several reasons, including the time and skill involved compared to the relative logistical ease of using mass-produced products instead.
“Polypills” or “combopills” are pills (capsules or tablets) containing multiple medications, manufactured to have combinations and dosages that would get prescribed together. For example, one particular “5-in-1 polypill” is targeted for heart-disease patients and it contains three blood pressure medications, a cholesterol reducer, and aspirin. Polypills are not presently common - especially for more than two drugs - partly because each permutation of drugs and dosages to be marketed must first be developed (including blends with appropriate inactive ingredients), trialed (for a suitable population), FDA-approved, manufactured, and stocked. To be worthwhile for a drug manufacturer, a particular drug/dosage permutation would need to prove suitable for a large number of people. Hence, manufactured polypills lack much personalizability. (In fact, even single-drug pills typically have very limited dosage options.) Alternatively, personalized polypills are possible via custom-compounding by a pharmacist, but very few pharmacies offer such service as it requires significant skill and time and current means have various challenges (e.g. precision, waste, etc.). Hence, combopills/polypills are simply not utilized much today, despite their potential to aid with the prevalent phenomenon of polypharmacy.
Much research has been done over many years on the potential to use inkjet printing based technologies for producing oral drug dosage forms, which may have applicability for facilitating patient-customized pills or polypills, including with customized formulations; Hewlett-Packard has published and patented significantly on inkjet-related approaches (e.g. U.S. Pat. Nos. 6,962,715, 7,727,576, and 7,707,964), which can offer precision and accuracy for spraying or jetting liquid drops of fluid API-in-solution onto an ingestible substrate such as a sheet or film, as well as for facilitating layer-by-layer deposition of powder substances (which is useful in making controlled-release tablets, via binding agents for “3-dimensional printing.” Ink-jet principles have also been adapted for dispensing liquid drugs into vials, or onto porous tablet substrates. All such ideas have been suggested to offer benefits for R&D, mass production, and customized dosage forms -including for multiple drugs. However, their dispensation is restricted to liquids, and to work with capsules they require an intermediary substrate.
In another development which is wholly unrelated to compounding or polypills, there have emerged some technologies to aid the manufacturability of new drugs for clinical trials. To manufacture drug capsules for clinical trial patients, traditionally this had required a choice between either developing a formulation with appropriate excipient(s) to permit automated manufacture (which was not precise enough to accurately handle raw drug substance without bulking), or else manually weighing the active pharmaceutical ingredient (API) for each capsule (requiring much time and skill, especially for potent substances). In recent years, certain manufacturing equipment has solved this dilemma and thus expedited many candidate drugs' manufacturability.
In order to allow automated manufacture without needing to develop a formulation, certain capsule filling machines have been developed which possess ability for “micro-dosing” very small amounts of powder with great precision, speed, and reliability. These are utilized to place raw API directly into capsules, in order to postpone the need to develop blends until initial studies can be done. This can save several months of delays before trials, thereby allowing failures to occur faster and with less sunk-cost. Simple formulations or select excipients can be included as well when desired, which may still involve significantly less mass than would otherwise be needed without micro-dosing. The most successful of such systems have used a “pepper-shaker” means (e.g. U.S. patent applications Ser. Nos. 11,571,169 and 12,035,037).
For example, the “Xcelodose” line of products by Capsugel can produce “API only” capsules - thus enabling sooner human trials without needing to first develop a formulation or perform compatibility or preformulation studies. Precise “micro-dosing” or “micro-filling” can be accurate to 100 micrograms-being of API directly, or in simple formulation (if preferred), or after treatment such as bulk densification or compaction (which may occasionally be needed), with minimal waste/attrition owing partly to the lack of a powder bed. Sometimes pre-processing steps (e.g. milling) may enhance performance but are not typically needed; other optional features for potential enhancement can include humidity control or thin metal prongs/baffles to minimize agglomeration. Also, capsule type/size and powder properties can vary significantly. Other systems featuring similar capability, using significantly different technological means, are available from other companies: Mettler-Toledo has the “Quantos” and Symyx has the “Powdernium,” which employ other precision-dispensing mechanisms. Known usage and exploitation of all such capabilities has only extended to research and development (R&D) applications & clinical trial product manufacturing-and only for single-drug products.